Environmental lead (Pb) exposure remains a major public health issue in the United States. Although the central nervous system (CNS) is the known target for Pb toxicity, the crucial mechanism(s) underlying Pb toxicity in developing brain is largely unclear. Our previous work indicates that Pb accumulates to a great extent in the choroid plexus (CP), a tissue constituting a barrier between blood and cerebrospinal fluid (CSF). Recently, we demonstrated that deposition of Pb in CP is associated with a significant decrease in CSF transthyretin concentration. It has been demonstrated that transthyretin in the CNS is solely manufactured and secreted by the CP and is primarily responsible for transport of thyroid hormones to the brain. It is also known that neonatal thyroid hormone deficiency could result in irreversible mental retardation. Taken together, we hypothesize that environmental Pb exposure induces a depression of CP TTR production (and/or secretion), which may impaired brain development by depriving it of thyroid hormones. The overall goals of our research proposal are to explore the role of the blood -CSF barrier in Pb-induced neurotoxicity. Our specific aims are to: (1) further characterize the effect and study the mechanism of Pb exposure on CSF TTR; (2) to determine whether decline in CSF TTR caused by Pb exposure leads to thyroid hormone deficiency in developing brain; and (3) to further characterize an in vitro system to investigate the mechanism whereby Pb alters TTR and iodothyronines in CSF and CP. In addition, we will explore if Pb exposure alters the concentrations of retinol binding protein (RBP) and retinoids in CSF and CP because RBP and TTR are secreted by CP and both are required for retinoid transport to CNS. This research should have significant public health implications: if Pb toxicity is indeed associated with the disturbance of brain concentrations of these macromolecules, then development of a new means of clinical therapy is possible. We believe that this study will likely create a highly fruitful avenue of research in environmental neurotoxicology.